Mono- and di-nicotinates of photosensitive quaternary ammonium compound and production thereof

ABSTRACT

THIS INVENTION IS CONCERNED WITH NOVEL MONO- AND DINICOTINATES OF CERTAIN PHOTOSENSITIVE QUATERNARY AMMONIUM COMPOUNDS PREPARED BY REACTING THE CORRESPONDING PHOTOSENSITIVE QUATERNARY AMMONIUM HALIDE WITH NICOTINIC ACID IN THE PRESENCE OF SILVER OXIDE. THE NOVEL NICOTINATES HAVE AN EXCELLENT WATER-SOLUBILITY AND PHARMACOLOGICAL AND BIOTICAL ACITVITIES WITH RELATIVELY LOW TOXICITY AND CAN BE USED AS MEDICAMENTS AS WELL AS ACTIVE INGREDIENTS OF VARIOUS HYGIENIC PREPARATIONS FOR EXTERNAL APPLICATIONS.

United States Patent 01' lice 3,562,261 Patented Feb. 9, 1971 MONO- ANDDI-NICOTINATES OF PHOTOSENSI- TIVE QUATERNARY AMMONIUM COMPOUND ANDPRODUCTION THEREOF Masaru Bauno and Shigeo Yasui, Okayama, OkayamaPrefecture, Japan, assiguors to Eisai Kabushiki Kaisha, Tokyo, Japan NoDrawing. Filed Jan. 22, 1968, Ser. No. 699,324

Int. Cl. C07d 31/36 US. Cl. 260240.1 2 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to a new class of water-soluble nicotinates ofparticular photosensitive compounds having pharmacological propertiessuitable for chemotherapy and for preparation of hygienic cosmetics.

Photosensitive compounds belonging to the group of cyanine andisocyanine dyestuffs in general have long been utilized asphotosensitizers in the industry of photography. Compounds such as1-ethyl-2-[w-5'-bromopyridyl-(Z') -aminovinyl]-6-rnethy1-pyridine-l-iodide having the formula:

exhibit powerful biotical activity. The remarkable biotical activitypresented by application of a minute amount of these compounds has beenwatched with keen interest and for many years efforts have been directedto utilize these compounds for hygienic and medical purposes. Theirconsiderable low Water solubility, however, makes it a decisive fault inthe utility of these compounds for the purposes.

It has been surprisingly found according to the present invention that anew class of novel nicotinates of certain photosensitive compoundshaving an increased solubility in alcohols and particularly in water canbe obtained by reacting nicotinic acid with a quaternary ammonium halideof the following general formula:

wherein R is an alkyl or an allyl group and X is a halogen atom andwherein A is a divalent radical selected from the group consisting of 10in which 2 is s, c or C(CH3)2;

in which Y is S or O; and

in which R is H or CH and wherein B is an atomic grouping directlyjoined to a carbon atom of the divalent radical A and selected from thegroup consisting of (CH=CH) -CH CH3 N t.

in which R" is alkyl and n equals 0 (zero) or 1,

in which R" is alkyl, Z is S or C(CH and n equals 0 in which R" isalkyl, and X is halogen atom;

in which R" is -halo-2-pyridyl or phenyl group substituted orunsubstituted with alkyl or alkoxy group or halogen atom in which X is ahalogen atom and In a preferred embodiment of the process of the presentinvention, the afore-mentioned novel nicotinates can successfully beprepared by reacting one of the quaternary ammonium halides of thespecified photosensitive compounds having the above-mentioned generalFormula I with nicotinic acid in a reaction medium such as an aqueousmethanol (1:1) and in the presence of freshly prepared silver oxideunder vigorous agitation. The silver halide which separates out as theprogression of the reaction is removed by filtration from the reactionmixture. The filtrate is evaporated to dryness, the solid reactionproduct remaining is recovered and purified through recrystallizationfrom ethanol, propanol, isopropanol, ace tone and the like.

All of the crystalline nicotinates of the specified photosensitivecompounds prepared in accordance with the process of the presentinvention are new compounds not given in the literature. They arecharacterized by their marked solubility in alcohol and in particular inwater as compared with those of the corresponding quaternary ammoniumhalide employed as starting material for the preparation thereof. Owingto the fact that the new compounds contain in their molecule the twomoieties of nicotinic acid and photosensitive compound, theyconcurrently exhibit both pharmacological activities of thesecomponents. They show remarkable antiallergic, antiedematic andantiseptic activities. They promote metabolism of cellular structure,hair growing and regeneration of skin tissue, wounds and the like.

The new compounds are therefore useful for chemotherapy of certaindiseases, such as allergy, edema, pyorrhoea and wounds due to chafing.It has also been found that since they show an excellent complementfixation in hibitor, they are useful for prophylaxis of anaphylaxy andallergy. The new compounds can be employed as active ingredient for thevarious hygienic cosmetics, such as hair tonic, skin tonic, hair lotion,skin lotion, antidandrutf and itch preventing preparations, hair pomadesin jelly and fluid forms, salve and the like.

The following examples are illustrative of the synthetic preparation ofthe novel compounds of this invention:

EXAMPLE 1 Preparation of 1-ethyl-6-methyl]w-(5-bromo-2-pyridylamino)vinyl]pyridine-l-nicotinate 4.46 grs. of1-ethyl-6-methyl[w-(5-bromo-2-pyridylamino)vinyl]pyridine-1-iodide andsilver oxide which has been freshly prepared from 1.8 grs. of silvernitrate and 0.4 gr. of caustic soda are reacted with 1.3 grs. ofnicotinic acid in 100 mls. of an aqueous methanol (1:1 by volume) undervigorous stirring for around 30-40 minutes. Silver iodide separated outis removed from the reaction mixture by filtration through a densefilter paper Without suction. The filtrate is evaporated under reducedpressure to dryness. The residue is redissolved in a small quantity ofethanol. To the solution thus obtained is added an amount of acetone tocrystallize out the product as yellow crystalline mass melting at 181 C.The resulting nicotinate is presented by the following formula:

EXAMPLE 2 Preparation of 3,3'-diethyl-2,2'-monomethin-benzothiazolocyanine-3-nicotinate 4.7 grs. of3,3'-diethyl-2,2'-monomethin-benzothiazolo cyanine-3-iodide and silveroxide freshly prepared from 1.8 grs. of silver nitrate and 0.4 gr. ofcaustic soda are reacted with 1.3 grs. of nicotinic acid in mls. of anaqueous methanol (1:1 by volume) under vigorous agitation for around30-40 minutes. Silver iodide precipitated out on the completion of thereaction is removed from the reaction mixture by filtration through adense filter paper without suction. The filtrate is evaporated on thewater bath to dryness. The residue is recrystallized from ethanol. Thereis obtained yellow crystalline powder melting at 243 4 C. The producthas the following formula:

(ll M CzHs 000 I 02115 EXAMPLE 3 pentamethin 'y-(2")-thiazolylthiazolocyanine-3,3-diiodide and silver oxide which has freshly beenprepared from 3.6 grs. of silver nitrate and 0.8 gr. of caustic soda arereacted with 2.6 grs. of nicotinic acid in mls. of an aqueous methanol(1:1 by volume) under vigorous agitation for around 30-40 minutes.Silver iodide which separates out as the progression of the reaction isremoved from the reaction mixture by filtration through a dense filterpaper under ambient pressure. The filtrate is evaporated under reducedpressure to dryness. The residue is purified from 15 cc. of acetone.There is thus obtained pure dinicotinate in a greenish crystallinepowder melting at 8085 C. The yield amounts to 4.2 grs. The product hasthe formula:

CH3 1 CH3 In the analogous manner as disclosed in the precedingexamples, there are obtained the monoand dinicotinates listed in thefollowing table starting from the correspondmg quaternary ammoniumhalides and nicotinic acid.

TAB LE Melting points, Products with formulae Appearances C Examples:

4. 3,ifdi-g-heptyl-4,4-dimetl1yl-2,2-monometl1inthiazolocyanine-3-nico-Yellow leaflets 132 um e.

5 3,3'-diethyl-4,4-dimethyl-2,2-trimetl1in-tl1iazoloeyauine-3-nicotinatePurple-blue needles 193-4 CHa/N 61,1,3,3,3,3-hexamethyl-2,2-trimethin-indocyanine-l-nicotinateRed-purple, metallic rustered crystal 166 CH3 CH3 CH3 CH3 73,3,3,4,4,4"-Hexamethyl-2,2-pentamethin-y-thiazolyl-(2)-thiazolo- Bluecrystal 148 cyanine3,3-dinicotinate.

/ CH=OHC=CHCH: m

N CH

8 l,1,1-triethyl-'y-quinolyl-(4) 4,4-pentamethin-quinocyanlne-l,1-Gold-yellow crystal 228 dinicotinate.

CzHa O O C- CZHB TABLE-C0ntlnuod Melting points, Products with formulaeAppearances C.

l-iso-pentyl-G-methyLZ-[w-(5-bromo-2"pyndylamino) -vinyl]-pyri(line-Yellowish brown powder 170-1 l-nicotinate.

3,4-dimethyl-2-(w-anilino) -viny1-oxaz0lc-3-nicollnatc Pale yellowpowder l-ethyl-6-methyl-2-(w-anllino)Vinyl-pyridine-l-nicotinate Yellowpowder CzHa O O 0- I 1-othyl-2-(w-anilinovlnyl)-pyrldinel-nicotlnateYellow powder C2 5 O O C- l3-ethyl-4-mothyl-2-(w-anllinovinyl)-thlaZo1e-3-nicotinato Pale yellowpowder 3-ethyl-4-methyl-2-(w-p-methoxyphonylamino)-thiazolo-3-nicotinateOrange yellow crystal S l -CH=CH-NH Q-oom on N czH5 00c ITABLE-Continued Melting points, Products with formulae Appearances C.

16 3-n-heptyl-4-methyl-2-(w-anilinovinyl)-thiaZo1e-3-nicotinate Yellowleaflet crystal 138-9 S I CH /N\ N-Cfllu, O O C I 173-ethyl-4-methyl-2-[w-(5-br0mo-2-pyridylamino)-vinyl]-thiazolc-3- Yellowcrystal 154-5 nicotiuate.

S CH=CHNI'I Br CH3 /N\ 02115 O O C 183-ethyl-4-methyl-2-[w-(p-chloropheuylamino)-vinyl]-thiaz0lc-3 Yellowleaflet crystal 185-6 nicotinate.

S l OH=CH-NHC1 CH3 /N\ C2115 O O C I 193-ethyl-4-methyl-[w-(5-chloro-2-pyridylamino)-vinyl]-tl1iaZo1o-3- Yellowpowder 142-3 nicotinate.

S OH=CH---NH Cl CH3 /N\ C2H 0 O C I 203-allyl-4-methyl-2-[w-(o-tolylamino)vinyl]-tl1iazole-3-nicotinatc Yellowpowder. 110-11 S (311 I CH=CHNH CHa/N\ /CH2 0 O O- I 011 1 CH2 N Theexcellent solubility in alcohols and in particular in water of thenicotinates according to the present invention will be seen from thedata given in the following table which has been obtained in comparisontests carried out with some typical products and the correspondingiodides. The figures of the data show the numbers of ml. of the solventsrequired for complete dissolution of one gram of the samples under test:

TABLE Corre- Corre- Corre- Correspondspondspondspond- Product of ngProduct of ing Product of ing Product of ing Example 1 1 iodide Example3 2 iodide Example 4 3 iodide Example 4 iodide Solvent Water 1 2, 850 2,850 110 200, 000 50 260 Ethanol 2 1, 200 1, 200 2, 800 9 200Propylcnglycol 2 200 200 10 200 43,4-dimethyl-Z-(w-anilino)-vinyl-oxaZ0le-3-nicotinate.

1 1 Acute toxicity of the typical nicotinates obtained by Example 1,that is,1-ethyl-6-methyl-[w-(5'-bromo-2'-pyridylamino)vinyl]pyridine-l-nicotinatewas observed by intravenous and per os administrations to healthy ddstrain adult mice weighing 18-20 grs. The results observed at the -6hours lapse of the administration are:

Intravenous injection: mg./ kg. LD50 Per os administration:

ministered per es in the amounts as shown hereinunder 25 table and thevolumes of the edema was measured by means of the string gauge in eachtime of 2, 3 and 4 hours lapse of the carrageenin injection. The resultsare tabu lated in table in which the anti-edematic effect (percent)shows the value obtained by dividing the figure of intensity of edemawith the figure of the intensity of edema in control and multiplying thequotient by 100:

TABLE Time after edema Antiinducadematic tion, Intensity of effect hoursedema percent Treatment:

200 mgI/kg--- 200 mgJkg 1 Exhibited significant difference from thecontrol in P=0.05.

A notable anti-edematic effect will be seen from table.

A significant inhibitory effect on passive cutaneous anaphylaxis(P.C.A.) exhibited by the same nicotinate compound was observed inguinea pig test. The skin dyes of the guinea pigs completely disappearedwhen 300-400 of the compound were administered. It was found that morepronounced inhibitory effect is observed when the administration waseffected concurrently with P.C.A. induction. Optimum effect was obtainedby administration in 60 minutes prior to the P.S."A. induction.

Following hygienic preparations are given as referential examples inwhich the novel nicotinates of the present invention are incorporated asactive ingredients, parts being by weight.

(A) Lotion Parts Lanolin 1.0 Propylenglycol monostearate 4.0 Higherfatty acid ester of cholesterol 7.0 5 Methyl oxybenzoate 0.1Propylenglycol 3.0 Water 85 3,4-dimethyl-2(w-anilino)vinyl-oxazole 3nicotinate (product of Example 0.01

10 Perfume, q.s.

T he ingredients are well mixed to form a homogeneous liquid.

(B) Cream Parts Glycerol monostearate 10.0 Vaseline 10.0 Liquid paraffin10.0 Lanolin 25.0 White bees-wax 5.0 Methyl p-oxybenzoate 0.15 Propylp-oxybenzoate 0.15 Water 39.0

Perfume, q.s.

1 ethyl 6 methyl [w (5' bromo 2pyridylamino)-vinyl]pyridine-l-nicotinate, (product of Example 1) 0.001The ingredients are well mixed under mild heat to form cream. (C) Hairtonic Parts Menthol 1.4 Resorcinol 0.5 Diethylstilbestrol 0.001 Ethanol80 Water 17 Glycerol 1 3,3 di n heptyl 4,4 dimethyl 2,2monomethinthiazolocyanin-3-nicotinate (product of Example 4) 0.001

Perfume, q.s.

The ingredients are well mixed to form a homogeneous liquid.

What we claim is:

1. 1 ethyl 6 methyl [w (5' bromo 2' pyridylamino)-vinyl]-pyridine-l-nicotinate.

2. 3,3,3" tri-n-heptyl 4,4',4"-trimethyl 2,2 pentamethin 'y thiazolylthiazolocyanin 3,3 dinicotinate.

References Cited UNITED STATES PATENTS 3,148,187 9/1964 Heseltine260240.4

OTHER REFERENCES JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R.

